Age of the Photon: The Billion Dollar Legacy of Britton Chance

1. Age of the Photon:The Billion Dollar Legacy of Britton Chance David Benaron, MD Founding (and Former) DirectorStanford Biophotonics Program Prof | Stanford School of Medicine and Chief Executive Officer | Spectros BC MemorialJune 2011

2. Where is the Need? • Optics “State of the Art” • Clinical Applications in Tissue Oximetry • Where is this going?

3. Which subject is dead?

4. Where is the Need? • Optics “State of the Art” • Clinical Applications in Tissue Oximetry • Where is this going?

5. Cells can be labeled and optically scanned ex vivo using Flow Cytometry Scanning of cells by Flow cytometry (Benaron et al, 1982)

6. Wanted to Reduce C-Section Rates, Improve Delivery Monitoring “There’s someone you need to meet”” Maria Delivoria-Papadopoulos

7. Optical Tomography: The Early Years Fiber Headband on head of infant Benaron, Cheong, et al. (1992)

8. Not Your Parents’ Optics:Optic Monitoring Includes Images, Reporters Optical sensors and markers can be tested in vitro then the same model is transferred to in vivo real time testing

9. BioluminescentEmittersImage In Vivo Peritonitis Pneumonia Lesions as small as 100 mm tagged with optical emitters can be seen from outside the body in real time. (Data: Xenogen and C. Contag, Stanford).

10. Optics Shows Highest Sensitivity

11. Optics Shows Highest Sensitivity

12. Optical Imaging Detects Single Stem Engraftment Hematopoesis from a single stem cell. Cao et al. Shifting foci of hematopoiesis during reconstitution from single stem cells. Proc Nat Acad Sci USA. 2004;101(1):221-226.

13. Optical Imaging Detects Single Stem Cells Optically labeled stem cells can be seen singly in vivo in bone marrow. Proc Natl AcadSci 2009 from University of Tsukuba, Japan and Univ. of Michigan Medical School.

14. 2008 Nobel in Chemistry Awarded for“in vivo Optical Contrast Agent” This prize was rightly BC’s -- Optical contrast -- In vivo imaging -- Spectroscopy -- Metabolism-based

15. "optical molecular imaging" OR "biophotonics“: > 1 million hits on Google

16. Cells can be detected in whole blood with ordinary pathology labels • 4 billion cells per cc of blood • Large volume cell imaging • 1 min collection, • 5 sec imaging time • Useful for: • − Circulating rare cell detection − Early sepsis detection Real-time imaging of labeled probes in 1-10 cc whole blood (Benaron et al, 2011 Project with Stanford Stem Cell Center, Sloan-Kettering Cancer Center)

17. Time to Change the Paradigm • Out with the Old Approach: • Blind, Watchful waitingEscalate care and monitoring whenever the patient gets ill • New Monitoring Approach: • More continuous, • Less Invasive monitoring. . .

18. Where is the Need? • Optics “State of the Art” • Clinical Applications in Tissue Oximetry • Where is this going?

19. Multispectral Pulse Oximetry 1980s: 2-wavelength pulse oximetry (2 wavelengths = 2 unknowns) • 1990s: multi-spectral pulse oximetry • (N wavelengths = N unknowns) • More accurate: Hemoglobins, Hct, Bilirubin… • Developed at Stanford • Introduced by Masimo • Public for $2B in late ‘00s

20. Original Data Oxy-Hb Deoxy-Hb Water Fit to Data Calculation of Oxygenation (NIRS) Spectral Fit 0.42 • n Wavelengths = n unknowns • Hemoglobin, fat, water all affect light in tissue • More wavelengths = more accuracy 0.4 0.38 0.36 Optical Density 0.34 0.32 0.3 0.28 0.26 0.24 650 700 750 800 850 900 950 1000 Wavelength (nm)

21. VLS, UV and NIRS Measure Different Regions of Tissue VLS NIRS

22. Noninvasive Tissue Oximetry The single most common cause of death in the hospital remains inability to supply sufficient oxygen to meet a tissues’ needs. * = multispectral T-Stat Monitor* Invos Monitor CAS Fore-Site* Hutchinson InSpectra Nonin

23. Multispectral Tissue Oximetry Correlates with Svo2 Background: This study compared multispectral VLS tissue Sto2 as measured by T-Stat to venous Svo2 as measured by Swan-Ganz (PAC) catheter at the Stanford University Medical Center, Palo Alto, CA. Methods: Subjects undergoing cardiac surgery on cardiopulmonary bypass were monitored using non-invasive VLS monitoring, sensitive to ischemia. Results: Swan values were measured and compared to Sto2 values (r2 = 0.94). Conclusions: VLS oximetry is correlated to measures of central venous oxygen. The relationship in of Svo2 to Sto2 in normoxia to hyperoxia appears to be linear

24. Multispectral Tissue OximetryCorrelates w/Svo2 to very low sats 80 70 60 50 40 30 20 Background: This study compared multispectral VLS tissue Sto2 as measured by T-Stat to venous Svo2 as measured by Swan-Ganz (PAC) catheter at the Stanford University Medical Center, Palo Alto, CA. Methods: Neonates were monitored using a VLS buccal probe for a period of 48-h post congenital open-heart procedures. Buccal readings were correlated to central SvO2 obtained from blood draws during this period. Results: 25 neonates monitored post op. Age 5 +/- 26 mo.; weight 6.4 +/- 4.3 kg). Conclusions: VLS multispectral tissue oximetry linearly correlated with SvO2. 20 30 40 50 60 70 80 Svo2 To be presented in the Am. Cardiology Congress 2011, Phoenix AZ

25. Correlates with Aortic Flow Blood flow in the Abdominal Aorta is highly correlated with serosal intestinal saturation during stepwise reductions and reestablishment of Aortic blood flow.

26. Imaging Necrotizing Enterocolitis 22±8% 68±4% 13±12% 68±3% 67±4% NIH Grants EB008355, CA126441 (Wong, Stanford, 2009)

27. Tissue Oximetry in Surgery Background: This study describes the normal post-operative recovery of perfusion to DIEP flaps. Methods: 41 DIEP flaps were monitored post-operatively using a VLS surface probe placed on the flap for a period of 60 h. No flaps required takeback, or experienced complete or partial flap loss. The mean and 95% CI was compared to a subsequent flap that was taken back for revision approximately 9 hours post surgery. Results: VLS provides a repeatable baseline for flap recovery, and may be able to detect reduced flap perfusion earlier than existing methods.

28. Monitoring with Contrast Agents

29. Dye in Lymph Frangioni slide Subcutaneous injection of fluorescent dye allows real time lymphatic tracing Frangioni et al (2007)

30. ICG Intraoperative Coronary Imaging System • A post-CABG intraoperative image shows no flow in graft (arrow) • Revised, and graft working prior to closure (from Novadaq, 2008)

31. Microsphere reporters can be monitored Implantable fluorescent microspheres made of polyethylene glycol that have an assay chemistry specific to glucose that changes the fluorescence work in conjunction with an external optical biosensor (LED light source) to enable noninvasive glucose monitoring.(Courtesy Texas A&M, 2008)

32. Britton and Britton • BB: Born July 24, 1999 BC: Born July 24, 1913

33. Where is the Need? • Optics “State of the Art” • Clinical Applications in Tissue Oximetry • Where is this going?

34. “Nano” will change everything we do ►The 21st Century is the Age of the Photon. In biology, biochemistry, and medicine, it was BC who led the way. ► Nanotechnology allows for sensors only tens of atoms across − Sensors will be too small to even see − Small sensors diffuse everywhere, report from anywhere − Enable massively-parallel multi-parametric monitoring − Nanobots will enable self-guiding sensor/treatments